NOVEL 1,2,4-OXADIAZOLE DERIVATIVES AS SELECTIVE BUTYRYLCHOLINESTERASE INHIBITORS: DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION

Alzheimer's disease (AD) is a progressive mental disorder that brings a huge economic burden to the healthcare systems. During this illness, acetylcholine levels in the cholinergic systems gradually diminish, which results in severe memory loss and cognitive impairments. Moreover, Butyrylcholinesterase (BuChE) enzyme participates in cholinergic neurotransmission regulation by playing a prominent role in the latter phase of AD. In this study, based on donepezil, which is an effective acetylcholinesterase (AChE) inhibitor, a series of 1,2,4-oxadiazole compounds were designed, synthesized and their inhibitory activities towards AChE and BuChE enzymes were evaluated. Some structures exhibited a higher selectivity rate towards BuChE in comparison to donepezil. Notably, compound 6n with an IC50 value of 5.07 mu M and an SI ratio greater than 19.72 showed the highest potency and selectivity towards BuChE enzyme. The docking result revealed that compound 6n properly fitted the active site pocket of BuChE enzyme, and formed desirable lipophilic interactions and hydrogen bonds. Moreover, according to in silico ADME studies, these compounds have proper potential for being developed as new oral anti-Alzheimer's agents.

Automated summary

The study synthesized a series of 1,2,4-oxadiazole compounds, among which compound 6n exhibited the highest potency and selectivity towards BuChE enzyme, potentially serving as new oral anti-Alzheimer's agents. The docking analysis showed that compound 6n properly fits the active site pocket of BuChE enzyme, forming desirable lipophilic interactions and hydrogen bonds. Additionally, in silico ADME studies suggested that these compounds have promising potential for development as new oral anti-Alzheimer's agents.